In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent with a potential role for the aryl hydrocarbon receptor (AhR)

Kamelia, Lenny; Haan, Laura de; Ketelslegers, Hans B.; Rietjens, Ivonne M.C.M.; Boogaard, Peter J.

doi:10.1016/j.toxlet.2019.08.001

Cited by 22 publications

(36 citation statements)

References 65 publications

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“…Also for the PS and GTLb extracts under study, their potencies in the EST with and without metabolism were compared (Figure ). The results obtained show that the DMSO extracts of the PS tested (sample 034‐HFO, 097‐DAE, 171‐GO, 175‐VTO, 186‐RAE) were able to inhibit the differentiation of ES‐D3 cells in the EST, as reported before (Kamelia et al, ). Interestingly, their PDT potency was not remarkably changed when ES‐D3 cells were exposed to the metabolite mixtures of the corresponding PS extracts (Figure A‐E).…”

Section: Resultssupporting

confidence: 84%

“…Recently we reported on the use of the EST to study PDT potency of DMSO extracts of PS and GTL products (Kamelia et al, , ). A highly significant correlation was found between the EST results and in vivo data ( R 2 = 0.97; Kamelia et al, ). Additionally, the results obtained in the EST correlated well with the three‐ to seven‐ring PAH content in the tested substances.…”

Section: Discussionmentioning

confidence: 99%

“…The performance of each fitted model was evaluated based on the scaled residuals, the Akaike's information criterion, the visual inspection of the model fit and the global goodness‐of‐fit, with fitted models showing a goodness‐of‐fit P ≥ .05 being accepted (Gift & Davis, ; Haber et al, ). The BMC values were selected from the accepted model with the lowest Akaike's information criterion (Haber et al, ; Kamelia et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…In the EST, the ability of test substances to inhibit the differentiation process of ES‐D3 cells is used as the endpoint to study PDT potency of test substances in vitro (Genschow et al, , ; Seiler & Spielmann, ). Recent studies in our lab showed the ability of the ES‐D3 cell differentiation assay of the EST to assess the PDT potencies of dimethyl sulfoxide (DMSO) extracts of PS (within and across categories with variable polycyclic aromatic hydrocarbon [PAH] content) and GTL products (containing no PAHs) (Kamelia et al, ; Kamelia et al, ). PDT potencies of different PS extracts, as evaluated in the ES‐D3 cell differentiation assay of the EST, appeared to be in line with their potencies observed in vivo (Kamelia et al, , ).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies in our lab showed the ability of the ES‐D3 cell differentiation assay of the EST to assess the PDT potencies of dimethyl sulfoxide (DMSO) extracts of PS (within and across categories with variable polycyclic aromatic hydrocarbon [PAH] content) and GTL products (containing no PAHs) (Kamelia et al, ; Kamelia et al, ). PDT potencies of different PS extracts, as evaluated in the ES‐D3 cell differentiation assay of the EST, appeared to be in line with their potencies observed in vivo (Kamelia et al, , ). GTL extracts tested negative in the EST, while all PAH‐containing PS extracts inhibited the differentiation of ES‐D3 cells into beating cardiomyocytes in a concentration‐dependent manner at non‐cytotoxic concentrations with a potency that was proportional to their three‐ to seven‐ring PAH content (Kamelia et al, , ).…”

Section: Introductionmentioning

confidence: 99%

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The role of metabolism in the developmental toxicity of polycyclic aromatic hydrocarbon‐containing extracts of petroleum substances

Kamelia

Haan

Spenkelink

et al. 2019

J of Applied Toxicology

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In vitro assays presently used for prenatal developmental toxicity (PDT) testing only assess the embryotoxic potential of parent substances and not that of potentially embryotoxic metabolites. Here we combined a biotransformation system, using hamster liver microsomes, with the ES‐D3 cell differentiation assay of the embryonic stem cell test (EST) to compare the in vitro PDT potency of two 5‐ring polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (BaP) and dibenz[a,h]anthracene (DBA), and dimethyl sulfoxide extracts from five PAH‐containing petroleum substances (PS) and a gas‐to‐liquid base oil (GTLb), with and without bioactivation. In the absence of bioactivation, DBA, but not BaP, inhibited the differentiation of ES‐D3 cells into beating cardiomyocytes in a concentration‐dependent manner. Upon bioactivation, BaP induced in vitro PDT, while its major metabolite 3‐hydroxybenzo[a]pyrene was shown to be active in the EST as well. This means BaP needs biotransformation to exert its embryotoxic effects. GTLb extracts tested negative in the EST, with and without bioactivation. The PS‐induced PDT in the EST was not substantially changed following bioactivation, implying that metabolism may not play a crucial role for the PS extracts under study to exert the in vitro PDT effects. Altogether, these results indicate that although some PAH require bioactivation to induce PDT, some do not and this latter appears to hold for the (majority of) the PS constituents responsible for the in vitro PDT of these complex substances.

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The role of metabolism in the developmental toxicity of polycyclic aromatic hydrocarbon‐containing extracts of petroleum substances

Kamelia

Haan

Spenkelink

et al. 2019

J of Applied Toxicology

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The role of receptor‐mediated activities of 4‐ and 5‐ring unsubstituted and methylated polycyclic aromatic hydrocarbons (PAHs) in developmental toxicity

Fang

Wang

Kramer

et al. 2023

J of Applied Toxicology

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The present study evaluated the aryl hydrocarbon receptor (AhR), estrogen receptor‐α (ER‐α), and retinoic acid receptor (RAR) mediated activities of nine 4‐ and 5‐ring unsubstituted and monomethylated polycyclic aromatic hydrocarbons (PAHs) using a series of Chemical‐Activated LUciferase gene eXpression (CALUX) assays. The potential role of these aforementioned receptors in relation to the developmental toxicity of these PAHs was further assessed in the zebrafish embryotoxicity test (ZET). The results show that all nine tested PAHs were AhR agonists, benz[a]anthracene (BaA) and 8‐methyl‐benz[a]anthracene (8‐MeBaA) were ER‐α agonists, and none of the tested PAHs induced ER‐α antagonistic or RAR (ant)agonistic activities. In the AhR CALUX assay, all the methylated PAHs showed higher potency (lower EC50) in activating the AhR than their respective unsubstituted PAHs, implying that the addition of a methyl substituent on the aromatic ring of PAHs could enhance their AhR‐mediated activities. Co‐exposure of zebrafish embryos with each individual PAH and an AhR antagonist (CH223191) counteracted the observed developmental retardations and embryo lethality to a certain extent, except for 8‐methyl‐benzo[a]pyrene (8‐MeBaP). Co‐exposure of zebrafish embryos with either of the two estrogenic PAHs (i.e., BaA and 8‐MeBaA) and an ER‐α antagonist (fulvestrant) neutralized embryo lethality induced by 50 μM BaA and the developmental retardations induced by 15 μM 8‐MeBaA. Altogether, our findings suggest that the observed developmental retardations in zebrafish embryos by the PAH tested may partially be AhR‐ and/or ER‐α‐mediated, whereas the RAR seems not to be relevant for the PAH‐induced developmental toxicity in the ZET.

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Evaluating the in vitro developmental toxicity potency of a series of petroleum substance extracts using new approach methodologies (NAMs)

Fang,

Rietjens,

Carrillo

et al. 2023

Arch Toxicol

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The present study evaluates the in vitro developmental toxicity and the possible underlying mode of action of DMSO extracts of a series of highly complex petroleum substances in the mouse embryonic stem cell test (mEST), the zebrafish embryotoxicity test (ZET) and the aryl hydrocarbon receptor reporter gene assay (AhR CALUX assay). Results show that two out of sixteen samples tested, both being poorly refined products that may contain a substantial amount of 3- to 7-ring polycyclic aromatic compounds (PACs), induced sustained AhR activation in the AhR CALUX assay, and concentration-dependent developmental toxicity in both mEST and ZET. The other samples tested, representing highly refined petroleum substances and petroleum-derived waxes (containing typically a very low amount or no PACs at all), were negative in all assays applied, pointing to their inability to induce developmental toxicity in vitro. The refining processes applied during the production of highly refined petroleum products, such as solvent extraction and hydrotreatment which focus on the removal of undesired constituents, including 3- to 7-ring PACs, abolish the in vitro developmental toxicity. In conclusion, the obtained results support the hypothesis that 3- to 7-ring PACs are the primary inducers of the developmental toxicity induced by some (i.e., poorly refined) petroleum substances and that the observed effect is partially AhR-mediated.

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In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent with a potential role for the aryl hydrocarbon receptor (AhR)

Cited by 22 publications

References 65 publications

The role of metabolism in the developmental toxicity of polycyclic aromatic hydrocarbon‐containing extracts of petroleum substances

The role of metabolism in the developmental toxicity of polycyclic aromatic hydrocarbon‐containing extracts of petroleum substances

The role of receptor‐mediated activities of 4‐ and 5‐ring unsubstituted and methylated polycyclic aromatic hydrocarbons (PAHs) in developmental toxicity

Evaluating the in vitro developmental toxicity potency of a series of petroleum substance extracts using new approach methodologies (NAMs)

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